Histopathology of NSCLC, IHC markers and ptnm classification

Transcription

1 ESMO Preceptorship on Non-Small Cell Lung Cancer November 15 th & 16 th 2017 Singapore Histopathology of NSCLC, IHC markers and ptnm classification Prof Keith M Kerr Department of Pathology, Aberdeen University Medical School, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, UK

2 The management of patients with lung cancer is becoming ever more dependant on a knowledge of the pathology of each patient s disease Know your enemy Sun Tzu, The Art of War.

3 The management of patients with lung cancer is becoming ever more dependant on a knowledge of the pathology of each patient s disease Lung cancer is NOT a single disease NOR is it just two diseases: Small Cell Carcinoma and Non-small Cell Carcinoma

4 The management of patients with lung cancer is becoming ever more dependant on a knowledge of the pathology of each patient s disease Lung cancer is NOT a single disease NOR is it just two diseases: Small Cell Carcinoma and Non-small Cell Carcinoma Non-Small Cell Carcinoma is NOT a specific biological entity more a classification of convenience driven by a lack of therapeutic choice

5 2015 WHO Classification of Lung Tumours (part 1!!) 1-2: Adenocarcinoma 1-2A Invasive adenocarcinoma 1-2B Variants of invasive adenocarcinoma 1-2C Minimally invasive adenocarcinoma 1-2D Preinvasive lesions 1-2D-i: Atypical adenomatous hyperplasia 1-2D-ii: Adenocarcinoma in situ 1-3: Squamous cell carcinoma 1-3A: Keratinizing and nonkeratinizing squamous cell carcinoma 1-3B: Basaloid carcinoma 1-3C: Preinvasive lesion: Squamous ca in situ 1-4: Neuroendocrine Tumours 1-4A: Small cell carcinoma 1-4B: Large cell neuroendocrine carcinoma 1-4C: Carcinoid tumors 1-4D: Preinvasive lesion: DIPNECH 1-5: Large cell carcinoma 1-6: Adenosquamous carcinoma 1-7: Sarcomatoid carcinoma 1-7A: Pleomorphic, spindle cell and giant cell carcinoma 1-7B: Carcinosarcoma 1-7C: Pulmonary blastoma 1-8: Other carcinomas 1-8A: Lymphoepithelioma-like carcinoma 1-8B: NUT-carcinoma

6 Small Cell Carcinoma of the Lung Nuclear features key to diagnosis Neuroendocrine markers and TTF1 IHC positive but not required for diagnosis Accurately diagnosed on cytology Aggressive disease, usually Stage 4 at presentation Therapeutic relevance chemotherapy choice radiotherapy strategy prognosis

7 So all those other, biologically diverse malignant diseases are NOT small cell carcinomas so we call them non-small cell carcinoma (NSCLC) Adenocarcinoma Squamous cell carcinoma Neuroendocrine tumours apart from SCLC Large Cell Carcinoma Adenosquamous Carcinoma Sarcomatoid Carcinomas Others

8 Atypical Adenomatous Hyperplasia AAH Invasive Adenocarcinoma Adenocarcinoma-in-situ There are at least two pathways of Lung Carcinogenesis Squamous carcinoma-in-situ Bronchial Squamous Dysplasia Invasive Squamous Cell carcinoma

9 Central Bronchial Carcinogenesis? The progenitor cells express p63, p40, Cytokeratins 5&6 Peripheral airway Carcinogenesis? The progenitor cells Express TTF1 The Terminal Respiratory Unit TRU

10 Adenocarcinoma Commonest subtype of lung cancer Associated with tobacco carcinogenesis Commonest subtype by far in never smokers Addictive oncogenic drivers are frequent in adenocarcinomas NOT associated with tobacco carcinogenesis Relatively inaccurately diagnosed by morphology alone ONLY 75-80% express TTF1 Therapeutic relevance Chemotherapy choice, Surgery choice Anti-angiogenic agents for safety and efficacy Testing for addictive oncogenic targets Testing strategy for immuno-oncology therapy?

11 Five histological patterns of adenocarcinoma: Most cases are mixtures, Pure forms are rare Papillary Lepidic Acinar Solid Micropapillary

12 Post operative survival vs predominant pattern in pulmonary adenocarcinoma AIS, MIA Lepidic Acinar Papillary High Grade Adenocarcinoma Histology and benefit from Adjuvant chemotherapy Solid, Micropapillary Tsao MS et al JCO 2015 Yoshizawa A et al. Mod Pathol 2011; 24, Stage 1 only Russell PA et al. J Thorac Oncol 2011; 6, Stages 1-3 Warth A et al. J Clin Oncol 2012; Mar 5 epub Stages 1-4

13 Squamous Cell Carcinoma Still common in populations who smoke Archetypal cancer of central, bronchial tobacco-driven carcinogenesis Rare in never smokers; rarely driven by addictive oncogene Relatively accurately diagnosed by morphology Most strongly express p63, p40, CK5/6 Therapeutic relevance Chemotherapy choice Toxicity and efficacy of anti-angiogeneics Choice of molecular testing Immunotherapy decisions

14 Neuroendocrine tumours other than SCLC Large Cell Neuroendocrine Carcinoma (LCNEC) High grade neuroendocrine carcinoma Strongly associated with tobacco carcinogenesis Molecularly similar to SCLC Generally a diagnosis for surgically resected tumours only, however.. Requires immunohistochemistry Therapeutic relevance Chemotherapy choice? Uncertainty due to diagnostic problems in advanced disease

15 Neuroendocrine tumours other than SCLC Typical Carcinoid Usually central bronchial tumour, Obstructive pneumonia Paradoxical lesion Low grade, wrong location Metastatic disease rare 10% regional nodes Distant metastases very rare Atypical Carcinoid Very rare, Relatively aggressive Mitoses & necrosis area dependent: 2mm 2 Diagnosis on small samples vs surgical material Therapeutic relevance Context important bronchial polyp or peripheral nodule Confusion with SCLC in biopsy or cytology

16 Large Cell Carcinoma ONLY diagnosed on surgical resection NEVER a diagnosis on small biopsy or cytology Most cases (66%) re-assigned as squamous or adenocarcinoma by IHC (WHO 2015) Therapeutic relevance Relatively aggressive tumour KRAS mutation dominant

17 Adenosquamous Carcinoma Relatively rare tumour Relatively aggressive tumour Peripheral or central? Requires minority component to comprise at least 10% of the lesion A surgical resection diagnosis Small biopsy or cytology suspicion only Morphology vs IHC Therapeutic relevance Manage like adenocarcinoma

18 Sarcomatoid Carcinoma Very rare lesions Pleomorphic carcinoma if >10% of lesion shows pleomorphic, spindle or giant cells Usually combined with squamous cell or adenocarcinoma Surgical resection for definitive diagnosis Therapeutic relevance Chemoresistant KRAS mutations relatively frequent Found in TKI-recurrent disease MET exon14 skipping mutations

19 The subtyping accuracy of NSCLCs in small biopsy and cytology was inaccurate by morphology alone Previous WHO classifications not designed for small samples This drove the adoption of the NSCLC-NOS diagnosis Which became a problem when therapy diversified by histology Most NSCLC-NOS diagnosis came from differentiated tumours 67% were adenocarcinoma when resected Edwards S et al 2000 Immunohistochemistry has transformed this diagnostic landscape NSCLC-NOS rates should be <10% cases

20 Bronchial Basal cells express p63, p40 and CK5/6 TRU epithelium expresses TTF1 Normal Normal AAH AIS Dysplasia Squamous CIS Invasive Squamous Cell Carcinoma (~100% express these markers) Invasive Adenocarcinoma (75-80% express TTF1)

21 Tumour cells express Nuclear p63 TTF1 positive in tumour cell nuclei NSCLC- probably squamous cell NSCLC probably adenocarcinoma

22 Subtyping NSCLC: How good? 6% 40% 25% Predictive IHC has levelled the playing field Better diagnosis possible on poorer specimens

23 Lung Cancer Classification and sample type WHO 2004 (et prev): intended for, and only applicable to, resected cases Small Cell Carcinoma Squamous Cell Carcinoma Adenocarcinoma Large cell carcinomas Sarcomatoid carcinomas Adenosquamous carcinomas Carcinoid tumours Salivary-type carcinomas WHO 2015: a simplified classification intended for small sample diagnosis Small Cell Carcinoma Squamous Cell Carcinoma Probable Squamous Cell Ca Adenocarinoma Probable Adenocarcinoma NSCLC-NOS NSCLC-NOS (null IHC) Carcinoid tumour Salivary-type (occasionally)

24 2 x 1mm tissue Fragments Testing algorithm Test tube tests Sections for DNA extraction EGFR, KRAS, BRAF mutation (NGS panels) On average only 20% is tumour Diagnose & subtype lung cancer Squamous Adeno etc Biomarker testing dictated by histology and protocol Morphology-based tests Immuno- Histochemistry IHC If required Sections for Biomarker IHC & FISH IHC should be used SPARINGLY for diagnosis ALK, ROS1 EGFR PD-L1

25 ptnm classification (7 th edition: adopted by UICC and AJCC) New proposals for TNM8 by IASLC from Jan 2017 Tumour Nodes Metastases ptnm based upon pathological examination

26 Carcinoma in situ: ptis Squamous Carcinoma In situ Adencarcinoma In situ - AIS

27 TNM8 pt1a(mi) Pulmonary nodule with small solid area surrounded by GGO

28 Most of this lesion is In situ disease Focus of Invasive Patterns of Adenocarcinoma This focus must be LESS THAN 5mm dia Minimally Invasive Adenocarcinoma MIA pt1a(mi) pt1a(mi)

29 9mm TNM7 26mm pt1a 2cm The lesion MUST NOT Involve a main bronchus pt1b >2cm but 3cm 18mm Unless

30 The lesion involving the main bronchus is a superficial spreading lesion with invasion limited to the bronchial wall pt1a

31 9mm pt1a 1cm TNM8 T1a T1b T1c 26mm pt1b >1cm but 2cm pt1c >2cm but 3cm 18mm

32 T2: tumours over 3cm but 7cm TNM7 46 mm pt2a >3cm 5cm pt2b >5cm 7cm 53 mm

33 TNM8 - T2: tumours over 3cm but 5cm 38 mm 46 mm pt2a >3cm 4cm pt2b >4cm 5cm

34 Pleural invasion upstages a tumour to pt2a PL1 PL2

35 pt2 TNM7 Regardless of size. This tumour is associated with atelectasis of a whole lobe Obstuctive pneumonitis extending to the hilar region but not involving the whole lung

36 pt2 TNM8 Regardless of size. This tumour is associated with atelectasis of a whole lobe Obstuctive pneumonitis extending to the hilar region Or involving the whole lung

37 Tumour > 2cm from carina TNM7 Small tumour but it involves main bronchus T2a

38 TNM8 Regardless of distance from the Carina as long as it is not involved Small tumour but it involves main bronchus T2a

39 TNM7 pt3 > 7cm 85mm

40 TNM8 T3 category SIZES changes to 5 cm but no greater than 7cm pt3 53 mm

41 Chest wall TNM7 pt3 Invasion of Mediastinal pleura Chest wall Superior sulcus Phrenic nerve Diaphragm Parietal pericardium Main bronchus within 2cm of carina Chest wall

42 pt3 Atelectasis or Obstructive Pneumonitis of the entire lung downgraded to T2 In TNM8

43 TNM7 TNM8 pt3 Same lobe Intrapulmonary metastases

44 pt3 Satellite nodules may be histological findings but there is no definition of a nodule

45 SVC Obstruction pt4 Invasion of Mediastinal structures Heart Great vessels Trachea Recurrent laryngeal nerve Oesophagus Vertebral body Carina

46 Left upper lobe Primary tumour Oblique fissure pt4 Different ipsilateral lobe Intrapulmonary metastases Left lower lobe metastasis Issues with Pulmonary Metastases versus synchronous Primary tumours

47 TNM8 >7cm is now T4 pt4 85mm

48 Which part or element of adenocarcinoma should be measured to determine T status? Adencarcinoma-in-situ Invasive tumour Lepidic growth

49 N3 Contralateral mediastinal or hilar nodes Scalene or supraclavicular nodes N2 N1 Stations N2 Subcarinal Station 7 pn disease identified by pathological examination Histology can define node positive disease

50 TNM7 M1a M1b Distant Metastases Liver, Adrenals, Bone, Brain, Skin, etc etc Cervical nodes above scalene are also M1 Contralateral lung metastases Pleural nodules Malignant pleural or pericardial effusion M1a or M1b defines Stage 4 disease

51 M1a TNM8 Contralateral lung metastases Pleural nodules Malignant pleural or pericardial effusion M1c Distant Metastases Liver, Adrenals, Bone, Brain, Skin, etc etc Cervical nodes above scalene are also M1 M1b Single extrathoracic metastasis is a single organ (incl lymph node) M1a or M1b defines Stage IVa M1c defines Stage IVb

52 TNM defines Stage Stage defines prognosis TNM7 TNM8

53 The management of patients with lung cancer is becoming ever more dependant on a knowledge of the pathology of each patient s disease Know your enemy Sun Tzu, The Art of War.